ReviewActa neuropathologica communications2026
Polymeric lysosome-targeting chimeras for extracellular α-synuclein degradation in Parkinson's disease.
Review in Acta neuropathologica communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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11 authors.
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Abstract
Disease progression in Parkinson's disease has been driven by extracellular α-synuclein prion-like seeding throughout the course of the disease and therefore not just by the intracellular accumulation of the protein in isolated aggregates. Current therapies utilizing PROTACs cannot address the extra-cellular effects of α-synuclein spreading in this manner. This article proposes PolyTACs (Polymeric Lysosome-Targeting Chimeras) as hybrid antibody-polymer conjugates which use neuronal exofacial thiol groups produced because of DJ-1/GSH dysregulation to capture α-synuclein pathological conformers before they can be derepressed (seeded pathological aggregates) into the cytoplasm. The hybridity of these antibodies (oligomers and fibrils) combined with pyridyl disulfide linkages in the multi-valent polymer allows these compounds to circumvent LTR co-option, and to be trafficked to lysosomes via a non-clathrin pathway. The delivery route for these agents is intended to be via intra-nasal, thereby bypassing many of the issues associated with delivery through the BBB. Delivery to patients will be guided by thiol profiling in cerebrospinal fluid to assist in inclusion-exclusion criteria for patients in prodromal trials. With these developments, it is anticipated that this new class of agent may provide a modular framework adaptable to other proteinopathies such as tau and TDP-43, pending further validation.
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